Metformin for Knee Osteoarthritis in Patients With Overweight or Obesity: A Randomized Clinical Trial

Abstract

Importance: Preclinical and preliminary human evidence suggests that metformin, a first-line treatment for type 2 diabetes, reduces inflammation, preserves cartilage, and improves knee pain in knee osteoarthritis.

Objective: To evaluate the effects of metformin on knee pain at 6 months in participants with symptomatic knee osteoarthritis and overweight or obesity.

Design, setting, and participants: Community-based randomized, parallel-group, double-blind, placebo-controlled clinical trial that used telemedicine to recruit and follow up participants remotely. Individuals with knee pain for 6 months or longer, a pain score greater than 40 mm on a 100-mm visual analog scale (VAS), and body mass index of 25 or higher were recruited from the community through local and social media advertisements in Victoria, Australia, between June 16, 2021, and August 1, 2023. Final follow-up occurred on February 8, 2024.

Interventions: Participants were randomly assigned to receive either oral metformin, 2000 mg/d (n = 54), or identical placebo (n = 53) for 6 months.

Main outcomes and measures: The primary outcome was change in knee pain, measured using a 100-mm VAS (score range, 0-100; 100 = worst; minimum clinically important difference = 15) at 6 months.

Results: Of 225 participants assessed for eligibility, 107 (48%) were randomized (mean age, 58.8 [SD, 9.5] years; 68% female) and assigned to receive metformin or placebo. Eighty-eight participants (82%) completed the trial. At 6 months, the mean change in VAS pain was -31.3 mm in the metformin group and -18.9 mm in the placebo group (between-group difference, -11.4 mm; 95% CI, -20.1 to -2.6 mm; P = .01), corresponding to an effect size (standardized mean difference) of 0.43 (95% CI, 0.02-0.83). The most common adverse events were diarrhea (8 [15%] in the metformin group and 4 [8%] in the placebo group) and abdominal discomfort (7 [13%] in the metformin group and 5 [9%] in the placebo group).

Conclusions and relevance: These results support use of metformin for treatment of symptomatic knee osteoarthritis in people with overweight or obesity. Because of the modest sample size, confirmation in a larger clinical trial is warranted.

Trial registration: ANZCTR Identifier: ACTRN12621000710820.

Figure 1.. Participant Flow in a Trial of Metformin for Symptomatic Knee Osteoarthritis in People With Overweight or Obesity

^aAbnormal blood test results included fasting glucose >6.0 mmol/L (>108 mg/dL), high-sensitivity C-reactive protein >5 mg/L, vitamin B₁₂ <200 pmol/L, or cholesterol <3.5 or >5.5 mmol/L (<135 or >212 mg/dL).

Figure 2.. Changes in 6-Month Knee Pain VAS Scores in Patients Treated With Metformin vs Placebo

Baseline knee pain scores on a 100-mm visual analog scale (VAS; score range, 0-100; 100 = worst; minimum clinically important difference = 15) are shown in ascending order for the metformin group and descending order for the placebo group. Lines connect each participant’s baseline score to their 6-month follow-up knee pain VAS score. An x indicates participants with a baseline score but no 6-month follow-up data. The box plots show the distribution of baseline and 6-month knee pain scores for each group. In the right panel, box plots for each treatment group show the distribution of changes in knee pain from baseline to 6 months, excluding participants with missing follow-up data. Each box spans the IQR, with the median shown as a solid line and the mean shown as a dashed line. Whiskers extend to the most extreme values within 1.5 times the IQR, and open circles represent individual data points outside this range.

Figure 3.. Knee Pain VAS Scores Over 6 Months in Patients Treated With Metformin vs Placebo Using Imputed Data

Participants self-reported knee pain over the past 7 days on a 100-mm visual analog scale (VAS; score range, 0-100; 100 = worst; minimum clinically important difference = 15).